Steroidogenic differentiation of human amniotic membrane-derived mesenchymal stem cells into a progesterone-/androgen-producing cell lineage by SF-1 and an estrogen-producing cell lineage by WT1-KTS.

Background: Sex steroid hormones, primarily synthesized by gonadal somatic cells, are pivotal for sexual development and reproduction. Mice studies have shown that two transcription factors, steroidogenic factor 1 (SF-1) and Wilms' tumor 1 (WT1), are involved in gonadal development. However, their role in human gonadal somatic differentiation remains unclear. We therefore aimed to investigate the roles of SF-1 and WT1 in human gonadal steroidogenic cell differentiation. Methods: Using a transient lentivirus-mediated gene expression system, we assessed the effects of SF-1 and WT1 expression on the steroidogenic potential of human amniotic membrane-derived mesenchymal stem cells (hAmMSCs). Results: SF-1 and WT1-KTS, a splice variant of WT1, played distinct roles in human steroidogenic differentiation of hAmMSCs. SF-1 induced hAmMSC differentiation into progesterone- and androgen-producing cell lineages, whereas WT1-KTS promoted hAmMSC differentiation into estrogen-producing cell lineages. Conclusion: Our findings revealed that SF-1 and WT1-KTS play important roles in human gonadal steroidogenic cell differentiation, especially during ovarian development. These findings may pave the way for future studies on human ovarian differentiation and development.

Meconium as an Analyte for Androgen Exposure: Analysis Through Varying Maternal-Fetal Biomarkers.

Meconium, the first stool produced by neonates, has been used as an analyte for exogenous fetal exposures. However, few studies have investigated the relationship between meconium and androgen exposure in utero. Here, we examine the associations of testosterone and dehydroepiandrosterone (DHEA) across maternal antenatal salivary testosterone, cord blood, meconium, and infant salivary testosterone. A total of 47 women with singleton, uncomplicated pregnancies, and their infants were included in this study. Participants were recruited from an academic obstetric clinic. Maternal saliva was collected at 36-weeks' gestation. Cord blood and meconium were collected at birth. Infant salivary testosterone was collected at 1 and 4 weeks of age. Multivariate model results showed that meconium testosterone was associated with neonatal testosterone at 1 (F = 5.62, p = 0.029) and 4 weeks (F = 4.28, p = 0.048) postnatal age; no sex differences were detected. This study suggests meconium is a valuable tool for evaluating endogenous androgen exposure and should be used in future studies to investigate the fetal hormonal milieu.

Oocyte-derived growth differentiation factor 9 suppresses the expression of CYP17A1 and androgen production in human theca cells.

OBJECTIVE: To investigate the direct effect of growth differentiation factor 9 (GDF9) on androgen production in human theca cells. DESIGN: Experimental study. SETTING: Tertiary hospital-based research laboratory. PATIENT(S): Women who underwent in vitro fertilization and intracytoplasmic sperm injections at our clinic were included in this study. INTERVENTION(S): Primary cultured human theca cells from women undergoing in vitro fertilization and intracytoplasmic sperm injection treatment were treated with GDF9, an activin receptor-like kinase 5 (ALK5) inhibitor, and a SMAD4 agonist. MAIN OUTCOME MEASURE(S): The expression of androgen synthesis-related genes StAR, CYP17A1, and LHCGR, levels of androstenedione and testosterone, phosphorylation of SMAD2/3, and the interaction between bone morphogenic protein-activated type II receptor and ALK5 were evaluated using reverse transcription-quantitative polymerase chain reaction, Western blot, enzyme-linked immunosorbent assays, and coimmunoprecipitation assays, respectively. RESULT(S): Growth differentiation factor 9 decreased StAR, CYP17A1, and LHCGR expression levels in human theca cells, which was prevented by treatment with the ALK5 inhibitor, and suppressed production of androgen in human theca cells. Growth differentiation factor 9 increased SMAD2/3 phosphorylation, and the ALK5 inhibitor also suppressed this effect. Bone morphogenic protein-activated type II receptor and ALK5 bound to each other after GDF9 stimulation. The SMAD4 agonist kartogenin also decreased messenger RNA levels of StAR and CYP17A1 and protein levels of StAR in human theca cells. CONCLUSION(S): Growth differentiation factor 9 can activate the bone morphogenic protein-activated type II receptor-ALK5-SMAD2/3 signaling pathway, suppress CYP17A1 expression, and decrease androgen production in human theca cells.

Development of a comprehensive open access "molecules with androgenic activity resource (MAAR)" to facilitate risk assessment of chemicals.

The increasing prevalence of endocrine-disrupting chemicals (EDCs) and their potential adverse effects on human health underscore the necessity for robust tools to assess and manage associated risks. The androgen receptor (AR) is a critical component of the endocrine system, playing a pivotal role in mediating the biological effects of androgens, which are male sex hormones. Exposure to androgen-disrupting chemicals during critical periods of development, such as fetal development or puberty, may result in adverse effects on reproductive health, including altered sexual differentiation, impaired fertility, and an increased risk of reproductive disorders. Therefore, androgenic activity data is critical for chemical risk assessment. A large amount of androgenic data has been generated using various experimental protocols. Moreover, the data are reported in different formats and in diverse sources. To facilitate utilization of androgenic activity data in chemical risk assessment, the Molecules with Androgenic Activity Resource (MAAR) was developed. MAAR is the first open-access platform designed to streamline and enhance the risk assessment of chemicals with androgenic activity. MAAR's development involved the integration of diverse data sources, including data from public databases and mining literature, to establish a reliable and versatile repository. The platform employs a user-friendly interface, enabling efficient navigation and extraction of pertinent information. MAAR is poised to advance chemical risk assessment by offering unprecedented access to information crucial for evaluating the androgenic potential of a wide array of chemicals. The open-access nature of MAAR promotes transparency and collaboration, fostering a collective effort to address the challenges posed by androgenic EDCs.

High androgen level during controlled ovarian stimulation cycle impairs endometrial receptivity in PCOS patients.

PCOS is one of the most common endocrine disorders among women of reproductive age. While the mechanism involved is not yet fully characterized. Our study aims to examine the pregnancy outcomes of embryo transfers in women with PCOS after pretreatment, and to explore the possible effect of high androgen levels on endometrial receptivity. Retrospective cohort study was conducted to analyze pregnancy outcomes among 2714 infertile women with tubal factor and 452 PCOS women. Endometrium samples were collected from 6 controls and 6 PCOS patients to detect the expression of endometrial receptivity marks. The implantation rate, clinical and ongoing pregnancy rates and live birth rate in women with PCOS followed fresh embryo transfers were obviously decreased even after the pretreatment. Similar pregnancy outcomes were found in frozen-thawed embryo transfer cycles between women with or without PCOS. Strikingly, serum total testosterone (TT) levels on trigger day were significantly higher in PCOS women. Women with high TT levels presented significantly lower clinical and ongoing pregnancy rates, and the expression of insulin-like growth factor binding protein 1 (IGFBP-1), and leukemia inhibitory factor (LIF) in the endometria decreased significantly as well. High doses of testosterone significantly down-regulated the expression of IGFBP-1 and LIF in Ishikawa cells. Although endocrine abnormalities had been improved before the controlled ovarian stimulation (COS) cycle started, higher serum TT levels were detected on the trigger day of the COS cycle in PCOS patients, which may contribute to the decreased fresh embryo implantation by impairing endometrial receptivity.

In vivo treatment with a non-aromatizable androgen rapidly alters the ovarian transcriptome of previtellogenic secondary growth coho salmon (Onchorhynchus kisutch).

Recent evidence suggests that androgens are a potent driver of growth during late the primary stage of ovarian follicle development in teleosts. We have previously shown that the non-aromatizable androgen, 11-ketotestosterone (11-KT), both advances ovarian follicle growth in vivo and dramatically alters the primary growth ovarian transcriptome in coho salmon. Many of the transcriptomic changes pointed towards 11-KT driving process associated with the transition to a secondary growth phenotype. In the current study, we implanted previtellogenic early secondary growth coho salmon with cholesterol pellets containing 11-KT and performed RNA-Seq on ovarian tissue after 3 days in order to identify alterations to the ovarian transcriptome in early secondary growth. We identified 8,707 contiguous sequences (contigs) that were differentially expressed (DE) between control and 11-KT implanted fish and were able to collapse those to 3,853 gene-level IDs, more than a 3-fold more DE contigs than at the primary growth stage we reported previously. These contigs included genes encoding proteins involved in steroidogenesis, vitellogenin and lipid uptake, follicle stimulating hormone signaling, growth factor signaling, and structural proteins, suggesting androgens continue to promote previtellogenic secondary growth.

Therapeutic potential of targeting AKR1C2 in the treatment of prostate cancer.

Prostate cancer development and progression are driven by androgens, and changes in androgen metabolic pathways can lead to prostate cancer progression or remission. AKR1C2 is a member of the aldo-keto reductase superfamily and plays an important role in the metabolism of steroids and prostaglandins. Alterations in the expression and activity of AKR1C2 affect the homeostasis of active androgens, which in turn affects the progression of prostate cancer. AKR1C2 reduces the highly active dihydrotestosterone to the less active 3α-diol in the prostate, resulting in lower androgen levels. Whereas the expression of AKR1C2 is significantly reduced in prostate cancer tissues relative to normal prostate tissues, this results in a weakening of the dihydrotestosterone metabolic inactivation pathway, leading to the retention of dihydrotestosterone in the prostate cancer cells, which promotes the progress of prostate cancer. Given the critical role of AKR1C2 in prostate cancer cells, targeting AKR1C2 for the treatment of prostate cancer may be an effective strategy. It has been demonstrated that curcumin and neem leaf extract effectively inhibit prostate cancer in vitro and in vivo by modulating AKR1C2.

Testosterone and resistance training improved physical performance and reduced fatigue in frail older men: 1 year follow-up of a randomized clinical trial.

OBJECTIVE: To improve health conditions among hypogonadal men ≥70 years of age using testosterone undecanoate (TU) injections, progressive strength training, and oral supplements of vitamin D, calcium, and protein. METHODS: This study is a 1-year follow-up of a double-blind RCT lasting 20 weeks, including 148 older men ≥70 years old with low testosterone levels and mobility problems. During 52 weeks, 4 groups received either testosterone therapy (TU) or progressive resistance training (Training), both (Combo), or no intervention (Controls). Physiotherapists supported the training groups until week 20, while these participants continued trained on their own during weeks 21 to 52. The main outcome measure was the 30-s chair stand test. RESULTS: The following numbers of participants completed the trial: 20 (Combo), 20 (Controls), 24 (TU), and 14 (Training). When examining 30-s chair stand test performance within each group at baseline, and at weeks 4, 20 and 52, only the Combo group improved (p = 0.001, Friedman Test). Compared to controls, only the Combo group experienced reduced fatigue and tiredness (p < 0.05). CONCLUSIONS: Fifty-two weeks of testosterone supplementation combined with progressive resistance training may enhance physical performance, alleviate fatigue, and had no notable detrimental impacts among males aged ≥70 suffering from mobility issues and testosterone insufficiency.Trial registration - Clinical Trials NCT02873559.

Decoding 11-oxygenated androgen synthesis: insights from enzyme gene expression and LC-MS/MS quantification.

BACKGROUND: Adrenal-origin and peripheral tissue-transformed 11-oxygenated androgens are recognized as significant androgens. However, our current understanding of the synthesis of 11-oxygenated androgens, including the organs and cell types involved, remains limited. METHODS: We performed comprehensive analyses on an extensive dataset of normal human tissues, which included bulk RNA data from 30 tissues, single-cell RNA sequencing (scRNA) data from 16 tissues and proteomics data from 29 tissues, to characterize the expression profiles of enzyme-encoding genes. To validate the findings, immunohistochemical and liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques were employed. RESULTS: Our investigation revealed that the gene expression levels of the enzymes HSD11B2 and AKR1C3 were notably elevated in the kidney and intestines. Intriguingly, within these organs, we observed an increasing trend in enzyme expression with age in women, while a decreasing trend was apparent in men. scRNA analysis revealed that HSD11B2 was predominantly expressed in collecting duct principal cells in the kidney, while AKR1C3 was primarily expressed in the proximal tubules. Intriguingly, nearly all epithelial cells in the intestine expressed these key enzymes. Further analysis using LC-MS/MS revealed that the kidney exhibited the highest levels of 11-ketoandrostenedione (11KA4) and 11-ketotestosterone (11KT) among the seven tissues examined, and substantial synthesis of 11KA4 and 11KT was also observed in the intestine. Finally, we developed the TransMap website (http://gxmujyzmolab.cn:16245/TransMap/) to provide comprehensive visualization of all currently available transcriptome data. CONCLUSION: This study offers an overarching perspective on tracing the synthesis of 11-oxygenated androgens in peripheral tissues, thereby providing valuable insights into the potential role of these androgens in humans.

The Role of 11-Oxygenated Androgens and Endocrine Disruptors in Androgen Excess Disorders in Women.

Polycystic ovary syndrome (PCOS) and idiopathic hirsutism (IH) are androgen excess disorders requiring the determination of classic androgen levels for diagnosis. 11-oxygenated androgens have high androgenic potential, yet their clinical value in those disorders is not clear. Additionally, the role of endocrine disruptors (EDs), particularly in IH, remains understudied. We analyzed 25 steroids and 18 EDs in plasma samples from women with IH, PCOS, and controls using LC-MS/MS. Cytokine levels and metabolic parameters were assessed. Comparisons included non-obese women with PCOS (n = 10), women with IH (n = 12) and controls (n = 20), and non-obese versus obese women with PCOS (n = 9). Higher levels of 11-oxygenated androgens were observed in women with PCOS compared to those with IH, but not controls. Conversely, 11-oxygenated androgen levels were lower in women with IH compared to controls. Cytokine levels did not differ between women with IH and controls. Bisphenol A (BPA) levels were higher in obese women with PCOS compared to non-obese women with PCOS. Bisphenol S occurrence was higher in women with PCOS (90%) compared to controls (65%) and IH (50%). Significant correlations were found between androgens (11-ketotestosterone, androstenedione, testosterone) and insulin and HOMA-IR, as well as between immunomodulatory 7-oxygenated metabolites of DHEA and nine interleukins. Our data confirms that PCOS is a multiendocrine gland disorder. Higher BPA levels in obese women might exacerbate metabolic abnormalities. IH was not confirmed as an inflammatory state, and no differences in BPA levels suggest BPA does not play a role in IH pathogenesis.

Androgens Suppress Corticosteroid Binding Globulin in Male Mice, Affecting the Endocrine Stress Response.

Biological sex affects the activity of the hypothalamus-pituitary-adrenal (HPA) axis. However, how androgen deprivation affects this axis remains largely unknown. In this study, we investigated the effect of androgen status on different components of the HPA axis in male mice. Two weeks of androgen deprivation did not affect total plasma corticosterone levels but led to increased pituitary ACTH levels. Stress-induced total plasma corticosterone levels were increased, whereas the suppression of corticosterone after dexamethasone treatment under basal conditions was attenuated. Androgen-deprived mice displayed a 2-fold increase in plasma levels of corticosteroid binding globulin (CBG). A similar increase in CBG was observed in global androgen receptor knock-out animals, compared to wild-type littermates. Androgen deprivation was associated with a 6-fold increase in CBG mRNA in the liver and enhanced transcriptional activity at CBG regulatory regions, as evidenced by increased H3K27 acetylation. We propose that the induction of CBG as a consequence of androgen deprivation, together with the unaltered total corticosterone levels, results in lower free corticosterone levels in plasma. This is further supported by mRNA levels of androgen-independent GR target genes in the liver. The reduction in negative feedback on the HPA axis under basal condition would suffice to explain the enhanced stress reactivity after androgen deprivation. Overall, our data demonstrate that, in mice, tonic androgen receptor activation affects CBG levels in conjunction with effects on gene expression and HPA-axis reactivity.

Androgen receptor monomers and dimers regulate opposing biological processes in prostate cancer cells.

Most prostate cancers express the androgen receptor (AR), and tumor growth and progression are facilitated by exceptionally low levels of systemic or intratumorally produced androgens. Thus, absolute inhibition of the androgen signaling axis remains the goal of current therapeutic approaches to treat prostate cancer (PCa). Paradoxically, high dose androgens also exhibit considerable efficacy as a treatment modality in patients with late-stage metastatic PCa. Here we show that low levels of androgens, functioning through an AR monomer, facilitate a non-genomic activation of the mTOR signaling pathway to drive proliferation. Conversely, high dose androgens facilitate the formation of AR dimers/oligomers to suppress c-MYC expression, inhibit proliferation and drive a transcriptional program associated with a differentiated phenotype. These findings highlight the inherent liabilities in current approaches used to inhibit AR action in PCa and are instructive as to strategies that can be used to develop new therapeutics for this disease and other androgenopathies.

Androgens contribute to sex bias of autoimmunity in mice by T cell-intrinsic regulation of Ptpn22 phosphatase expression.

Autoimmune diseases such as systemic lupus erythematosus (SLE) display a strong female bias. Although sex hormones have been associated with protecting males from autoimmunity, the molecular mechanisms are incompletely understood. Here we report that androgen receptor (AR) expressed in T cells regulates genes involved in T cell activation directly, or indirectly via controlling other transcription factors. T cell-specific deletion of AR in mice leads to T cell activation and enhanced autoimmunity in male mice. Mechanistically, Ptpn22, a phosphatase and negative regulator of T cell receptor signaling, is downregulated in AR-deficient T cells. Moreover, a conserved androgen-response element is found in the regulatory region of Ptpn22 gene, and the mutation of this transcription element in non-obese diabetic mice increases the incidence of spontaneous and inducible diabetes in male mice. Lastly, Ptpn22 deficiency increases the disease severity of male mice in a mouse model of SLE. Our results thus implicate AR-regulated genes such as PTPN22 as potential therapeutic targets for autoimmune diseases.

dmrt1 Is Responsible for Androgen-Induced Masculinization in Nile Tilapia.

17α-Methyltestosterone (MT) is a widely used androgen for all-male fish production in aquaculture. However, the molecular mechanism underlying MT-induced masculinization remains unclear. In this study, we aim to identify the key gene responsible for MT-induced masculinization using the Nile tilapia (Oreochromis niloticus) amhy, dmrt1, and gsdf mutants, which exhibit male-to-female sex reversal. Nile tilapia fry from these three mutant lines were treated with 50 µg/g MT from 5 to 30 days after hatching (dah). The results showed that amhy and gsdf mutants, but not dmrt1 mutants, were masculinized by the MT treatment. Gonadal transcriptome analysis revealed that genes involved in steroidogenesis and germ cell development in MT-treated dmrt1 mutants exhibited a similar expression pattern to that of the wild type (WT) XX. In addition, the dmrt1 mutants cannot be masculinized by co-treatment with MT and the aromatase inhibitor fadrozole. The MT treatment completely blocked early steroidogenic enzyme (Star2, Cyp17a2, and Cyp19a1a) expression independent of amhy, gsdf, and dmrt1. A luciferase analysis showed that MT directly suppressed basal and Sf-1-activated cyp19a1a promoter activity through ara and arb in cultured HEK293 cells. Furthermore, MT treatment inhibited germ cell proliferation in amhy and gsdf mutants but not in dmrt1 mutants. Consistently, dmrt1 expression was induced in MT-treated WT XX, -amhy, and -gsdf mutants. Taken together, these results suggest that dmrt1 is indispensable for MT-induced masculinization in Nile tilapia and that MT functions by inhibiting early steroid synthesis and activating dmrt1 to promote testis development.

[Impacts of testis aging on overall health: Advances in studies].

The testis, as one of the important reproductive organs in men, has two major functions of secreting androgens and producing sperm. Androgen and spermatogenesis are the key factors for the evaluation of the testicular function. The lack of androgen or the decline of spermatogenic function is both a symbolic manifestation and a "product" of testis aging. In order to gain a deeper insight into the relationship between testis aging and overall health, this article reviews the relevant literature based on the correlation of androgen deficiency with various systemic diseases and the belief in the impacts of testis aging on the health of the cardiovascular and nervous systems through different channels, the development and progression of metabolic diseases, orthopedic diseases, PCa, kidney disease, peptic ulcer and other diseases. All these suggest that adequate attention should be paid to the studies of male reproductive health and its impact on overall health, so as to provide some new ideas and evidence for clinical diagnosis and treatment of relevant conditions.

Epigenome-wide impact of MAT2A sustains the androgen-indifferent state and confers synthetic vulnerability in ERG fusion-positive prostate cancer.

Castration-resistant prostate cancer (CRPC) is a frequently occurring disease with adverse clinical outcomes and limited therapeutic options. Here, we identify methionine adenosyltransferase 2a (MAT2A) as a critical driver of the androgen-indifferent state in ERG fusion-positive CRPC. MAT2A is upregulated in CRPC and cooperates with ERG in promoting cell plasticity, stemness and tumorigenesis. RNA, ATAC and ChIP-sequencing coupled with histone post-translational modification analysis by mass spectrometry show that MAT2A broadly impacts the transcriptional and epigenetic landscape. MAT2A enhances H3K4me2 at multiple genomic sites, promoting the expression of pro-tumorigenic non-canonical AR target genes. Genetic and pharmacological inhibition of MAT2A reverses the transcriptional and epigenetic remodeling in CRPC models and improves the response to AR and EZH2 inhibitors. These data reveal a role of MAT2A in epigenetic reprogramming and provide a proof of concept for testing MAT2A inhibitors in CRPC patients to improve clinical responses and prevent treatment resistance.

Pre-receptor regulation of 11-oxyandrogens differs between normal and cancerous endometrium and across endometrial cancer grades and molecular subtypes.

Background: Endometrial cancer (EC) is a prevalent gynecological malignancy globally, with a rising incidence trend. While classic androgens have been implicated with EC risk, the role of their 11-oxygenated metabolites is poorly understood. Here, we studied 11-oxyandrogen formation from steroid precursors in EC for the first time. Methods: We performed in vitro studies on a panel of four EC cell lines of varying differentiation degree and molecular subtype and a control cell line of normal endometrium to assess 11-oxyandrogen formation from steroid precursors. We also characterized the transcriptomic effects of dihydrotestosterone (DHT) and 11-keto-DHT on Ishikawa and RL95-2. Key molecular players in 11-oxyandrogen metabolism and action were explored in endometrial tumors using public transcriptomic datasets. Results: We discovered that within endometrial tumors, the formation of 11-oxyandrogens does not occur from classic androgen precursors. However, we observed distinct regulatory mechanisms at a pre-receptor level in normal endometrium compared to cancerous tissue, and between low- and high-grade tumors. Specifically, in vitro models of low-grade EC formed higher levels of bioactive 11-keto-testosterone from 11-oxyandrogen precursors compared to models of noncancerous endometrium and high-grade, TP53-mutated EC. Moreover, the potent androgen, DHT and its 11-keto homologue induced mild transcriptomic effects on androgen receptor (AR)-expressing EC model, Ishikawa. Finally, using public transcriptomic datasets, we found HSD11B2 and SRD5A2, coding for key enzymes in steroid metabolism, to be associated with better disease-specific survival, whereas higher intra-tumoral AR expression correlated with lower recurrence in TP53-wt tumors. Conclusions: The intra-tumoral metabolism of 11-oxyandrogen precursors is characteristic for low-grade EC of non-TP53-alt molecular subtypes. Our findings support further exploration of circulating 11-oxyandrogens as prognostic biomarkers in EC.

Androgen deprivation exacerbates AD pathology by promoting the loss of microglia in an age-dependent manner.

AIMS: Microglial cells are integral to the pathogenesis of Alzheimer's disease (AD). The observed sex disparity in AD prevalence, with a notable predominance in women, implies a potential influence of sex hormones, such as androgens, on disease mechanisms. Despite this, the specific effects of androgens on microglia remain unclear. This study is designed to delineate the interplay between androgens and the survival and inflammatory profile of microglial cells, as well as to explore their contribution to the progression of AD. METHODS AND KEY FINDINGS: To create a chronic androgen deficiency model, 3-month-old wild-type (WT) mice and APP/PS1 mice underwent bilateral orchiectomy (ORX), with age-matched sham-operated controls. Cognitive and memory were evaluated at 5 and 12 months, paralleled by assessments of amyloid-beta (Aß) and microglial morphology in hippocampal and cortical areas. The ORX treatment in mice resulted in diminished microglial populations and morphological alterations, alongside an increase in Aß plaques and a concomitant decline in cognitive performance that exacerbated over time. In vitro, dihydrotestosterone (DHT) was found to stimulate microglial proliferation and ameliorate Aß1-42-induced apoptosis. SIGNIFICANCE: These findings suggested that androgens may exert a protective role, maintaining the normal proliferation and functionality of microglial cells. This preservation could potentially slow the progression of AD. As a result, our study provided a conceptual framework for the development of novel therapeutic strategies for AD.

Adolescent exposure to bisphenol-a antagonizes androgen regulation of social behavior in male mice.

Social behavior is sexually dimorphic, which is regulated by gonadal hormones in the brain. Our recent study found that exposure to low doses of bisphenol-A (BPA) during adolescence, permanently alters social behavior in adult male mice, but the underlying mechanisms remain unclear. Using adolescent gonadectomy (GDX) male mice with testosterone propionate (TP, 0.5 mg/kg) supplement (TP-GDX), this study showed that BPA antagonized promoting effects of TP on social interaction, sexual behavior, and aggression in GDX mice. BPA eliminated the reversal effects of TP on GDX-induced decrease in the number of immunoreactive to arginine vasopressin (AVP-ir) neurons in the medial amygdala (MeA) and the levels of AVP receptor 1a (V1aR) in the MeA and the nucleus accumbens (NAc). In addition, BPA removed down-regulation in the levels of dopamine (DA) transporter (DAT) and DA receptor 1 (DR1) in the NAc of TP-GDX mice. BPA exposure reduced testosterone (T) levels in the brain and serum and the expression of androgen receptor (AR) protein in the amygdala and striatum of sham-operated and TP-GDX males. These results suggest that adolescent exposure to BPA inhibits regulation of androgen in AVP and DA systems of the brain regions associated with social behavior, and thus alters social behaviors of adult male mice.